The human immunodeficiency viruses HIV-1 and HIV-2 and the closely related simian immunodeficiency viruses (SIV), all use the CD4 molecule as a receptor during infection. Other cellular molecules have long been suspected to form an essential component of the cellular HIV receptor; however, the nature of such cellular molecules was not known until the discovery of fusin (Feng et al., 1996, Science 272:872-876; Maddon et al., 1986, Cell 47:333-348; Dragic et al., 1995, J. Virol. 69:1013-1018; Clapham et al., 1992, J. Virol. 66:3531-3537; Chesebro et al., 1990, J. Virol. 64:215-221; Stefano et al., 1993, J. Virol 67:6707-6715; Hoxie et al., 1988, J. Virol. 62:2557-2568).
Recently, two molecules, fusin, which is now known as CXCR4 (also known as Lestr, LCR-1, and HUMSTR) and CCR5, which are members of the chemokine receptor family of proteins, have been shown to function with CD4 as coreceptors for HIV-1 isolates that are tropic for T-cell lines or macrophages, respectively (Feng et al., 1996, Science 272:872-876; Alkhatib et al., 1996, Science 272:1955-1958; Deng et al., 1996, Nature 381:661-666; Dragic et al., 1996, Nature 381:667-673). Other molecules in this family including CCR3 and CCR2b, also appear to function as cofactors for some HIV-1 isolates (Doranz et al., 1996, Cell 85:1149-1158; Berson et al., 1997, J. Virol. 71: 1692-1696; Choe et al., 1996, Cell 85:1135-1148). Moreover, recent studies have also implicated CCR5 and CXCR4 as coreceptors for isolates of simian immunodeficiency viruses (SIV) and HIV-2, respectively. This, indicates that the use of chemokine receptors is a general property of all human and nonhuman lentiviruses.
In addition to studies on CD4-dependent infection, several reports have demonstrated that some HIV isolates are capable of infecting lymphoid cells (Clapham et al., 1992, supra; Clapham, 1991, Rev. in Med. Virol. 1:51-58; McKnight et al., 1994, Virology 201:8-18) or non-lymphoid cells (Clapham et al., 1992 supra; Harouse et al., 1991, Science 253:320-323; Tateno et al., 1989, Proc. Natl. Acad. Sci. USA86:4287-4290; Li et al., 1990, J. Virol. 64:1383-1387; Ikeuchi et al., 1990, J. Virol. 64:4226-4231) in the absence of CD4. Although infection of CD4-negative cells generally proceeds slowly and without cytopathic effects, some isolates of HIV-2 infect CD4-negative cells rapidly and cause extensive cell fusion (Clapham et al., 1992, supra). The highly cytopathic nature of these infections has suggested that these isolates can utilize one or more receptors other than CD4 with high efficiency.
HIV-1 strains exhibit distinct tropisms for CD4-positive cells. Macrophage tropic (M-tropic) strains of HIV-1 enter and replicate in macrophages and primary T cells but generally fail to enter T cell lines. These isolates characteristically do not induce multinucleated giant cells when cultured with certain immortalized T cell lines and are generally non-syncytium inducing (NSI). In contrast, T cell tropic strains fail to enter macrophages efficiently but readily infect primary T cells and induce syncytia (SI) on some T cell lines (Fauci et al., 1996, Nature 384:529-534). This difference in cell tropism has been shown to correlate with disease progression in that HIV strains isolated from individuals early in the course of their infection are M-tropic and NSI, while viruses isolated from individuals with advanced immunodeficiency are typically T-tropic and SI.
CXCR4 is a cellular protein which in conjunction with CD4, forms a functional cellular receptor for entry of certain strains of HIV into cells. This protein is a member of a family of molecules that bind chemokines which are involved in the trafficking of T cells and phagocytic cells to areas of inflammation (Power and Wells, 1996, Trends Pharmacol. Sci. 17:209-213). The chemokines MIP-alpha and MIP-beta and RANTES all bind to CCR5 while stromal cell derived factor (SDF-1) binds to CXCR4 (Bluel, et al., 1996, Nature 382:829-832; Oberlin et al., 1996, Nature 382:833-835). Recent reports have indicated that the viral envelope glycoprotein gp120 interacts directly with chemokine receptors (Lapham et al., 1996, Science 274:602-605; Moore, 1997, Science 276:51; Wu et al., 1996, Nature 384:179-183; Hesselgesser et al., 1997, Current Biology 7:112-121), generally at a step following CD4 binding.
CXCR4 fulfills the requirements of an HIV receptor co-factor. It renders a number of murine, feline, simian, quail, and hamster cell lines, as well as human cell lines, which cells are normally resistant to HIV-1 entry, fully permissive for HIV-1 env mediated syncytia formation. In addition, the T cell tropic HIV strain HIV-1 IIIB, is capable of infecting both murine and feline cells which co-express human CD4 and CXCR4. However, the macrophage tropic strain Ba-L, is not capable of infecting cells which co-express both CXCR4 and CD4. These results suggest that CXCR4 can serve as a co-factor for T-tropic, but not M-tropic, HIV-1 strains (Feng et al., 1996, supra). Moreover, the finding that change from M to T-tropic viruses over time in infected individuals correlates with disease progression suggests that the ability of the viral envelope to interact with CXCR4 represents an important feature in the pathogenesis of immunodeficiency and the development of full blown AIDS.
Current anti-HIV therapy includes the use of compounds which inhibit various aspects of HIV replication in a cell such as inhibition of replication and/or transcription of viral nucleic acid and inhibition of protein processing. While these therapies, particularly when used in combination with one another, are effective, they are frequently short-lived in that viral strains rapidly develop that are resistant to one or more of the compounds used. There therefore remains an acute need to develop additional therapies and strategies for preventing HIV infection in humans.